Chronic cocaine has been shown to switch CRF2R modulation of glutamatergic transmission from inhibitory to excitatory in the lateral septum (Liu et al., 2005), but the consequences of this plasticity for stress responses and drug seeking remain to be determined. The lateral septum has long been held to play a role in emotional processes and stress responses, and neurons within the lateral septum promote active stress coping behavior and inhibit HPA axis responses to stress (Singewald et al., 2011). CRF receptors within the lateral septum are predominantly of the CRF2 type, and blockade of these receptors has been shown to result in a specific reduction in stress-induced behavior, while their stimulation promotes anorexia and anxiety-like behavior (Bakshi et al., 2007). Modulation of lateral septum function by CRF2 receptors may, however, also impact drug seeking driven by rewarding, appetitive processes, because a pathway that originates in the lateral septum drives hypothalamic hypocretin/orexin neurons and is necessary for cocaine conditioned place preference (Sartor and Aston-Jones, 2012).
